The discipline of Transfusion Biology and medicine must continually address the problems of protein polymorphisms and the immune responses they elicit. Not only are these responses directed at transfused plasma and cell-bound determinants, but they are also directed at transfusion-transmitted diseases, such as hepatitis C, or transplantation antigens. Often the immune response is successful and the offending organism or the foreign antigen is eliminated. in some instances, a humoral response is directed by the mother against the fetus, sometimes with serious consequences as occurs with neonatal alloimmune thrombocytopenia, or antibodies are generated against foreign epitopes transfused to naive recipients with genetic absence of normal regulatory proteins such as to factor VIII in hemophilia A. In certain instances, polymorphisms result in abnormal function because of defective assembly of structural and functional proteins (Glanzmann's thrombasthenia, von Willebrand disease, Scott Syndrome). Still others are due to the alteration of structural proteins induced by drugs (heparin-induced thrombocytopenia). Often the polymorphic stimulus is recognized in the context of a polymorphic immune response, which is guided down pathways of immune tolerance or rejection. Even less understood is the immune response of patients infected with hepatitis C because the host immune system is not effective in eliminating the offending virus. Learning how the body becomes tolerant to certain foreign materials, including even HCV, can help us design strategies to deal with immunorejection that must be overcome, for example, when dealing with hemophilic patients who develop antibodies to Factor VIII. These responses are daily problems that are faced in the practice of transfusion medicine. This Program Project is comprised of four projects that deal with structural and functional polymorphisms and three projects that study the mechanisms of immune responsiveness. Each project has mechanistic and functional synergisms with the other projects. Using sophisticated molecular and cellular techniques, a comprehensive, integrated program has been assembled to study: 1) immune responses following transfusion, 2) polymorphic hemostatic deficiencies that require treatment with transfusion products, and 3) molecular and cellular alterations that occur during physiologic and pathologic development. Information gained from these studies will contribute to methods of diagnosing diseases, understanding complex biologic processes that must currently be treated by cellular or protein replacement therapy, new therapies that may reduce the need for transfusion therapy, or changes in the practice of transfusion medicine t minimize complications such as transfusion-transmitted diseases or acquired FVIII inhibitors. Although basic research techniques are utilized, the ultimate benefit will come from the close interaction with the clinical transfusion program where changes in therapy can impact on the development of disease or its complications.